Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells
Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells
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DOI：
10.1038/nm1417
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发表时间：
2006-06-01
期刊：
影响因子：
82.9
通讯作者：
Lapidot, Tsvee
中科院分区：
文献类型：
--
作者：
Kollet, Orit;Dar, Ayelet;Lapidot, Tsvee
在此，我们研究了骨吸收破骨细胞在造血祖细胞的内稳态及应激诱导动员中的潜在作用。不同的应激情况诱导了骨中富含干细胞的骨内膜区域破骨细胞（OCLs）的活性、蛋白水解酶的分泌以及祖细胞的动员。用核因子κB受体活化因子配体（RANKL）特异性刺激OCLs，主要以依赖趋化因子受体4（CXCR4）和基质金属蛋白酶 - 9（MMP - 9）的方式将未成熟祖细胞招募到循环中；然而，在破骨细胞骨黏附和吸收存在缺陷的年轻雌性蛋白酪氨酸磷酸酶ε（PTP epsilon）敲除小鼠中，RANKL并未诱导动员。用降钙素抑制OCLs可减少内稳态、粒细胞集落刺激因子（G - CSF）动员以及应激情况下祖细胞的流出。RANKL刺激的骨吸收性OCLs还减少了骨内膜处的干细胞龛成分——基质细胞衍生因子 - 1（SDF - 1）、干细胞因子（SCF）和骨桥蛋白，这与祖细胞动员有关。最后，主要的骨吸收蛋白酶——组织蛋白酶K也能裂解SDF - 1和SCF。我们的研究结果表明，OCLs参与了选择性祖细胞招募，这是内稳态和宿主防御的一部分，将骨重塑与造血调控联系起来。
Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts ( OCLs) along the stem cell-rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9-dependent manner; however, RANKL did not induce mobilization in young female PTP epsilon-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor ( SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.